Roles of cytochrome P-450 enzymes in chemical carcinogenesis and cancer chemotherapy.

Studies involving the metabolism of chemical carcinogens were important in the discovery and initial characterization of the cytochrome P-450 enzyme system. The Millers and their associates identified NADPH-dependent microsomal enzymes involved in the biotransformation of azo dyes (1, 2). These reactions, reduction and mixed-function oxidation, were also found to be important in the processing of many other carcin ogens, as well as drugs and steroids. Subsequent work led to the identification of the hemoprotein P-4503 as the terminal oxidase involved in such microsomal mixed-function oxidations (3,4). Other early studies revealed that administration of many different chemicals to animals could alter the metabolism of carcinogens (5-7). As we know now, many forms of P-450 exist and the expression of these enzymes is influenced by the com pounds which are given to the animals. Administration of the carcinogenic polycyclic hydrocarbon 3-methylcholanthrene to rats and analysis of the liver microsomes provided some of the early evidence that multiple forms of P-450 exist (8, 9). Since that time, a great deal of effort has been concentrated upon understanding the biochemistry of these P-450 enzymes, in terms of how they catalyze reactions and how their expression is regulated. Although much of the focus regarding P-450 proteins has involved their contributions to the metabolism of steroids and drugs, considerable effort is still directed towards understanding the roles of P-450s in carcinogen metabolism. The characteristics of P-450 enzymes will not be reviewed at length here.4 The microsomal enzymes are found in most tissues but are concentrated in liver. All have characteristic ferrouscarbon monoxide complex Soret peaks near 450 nm, have montimene molecular weights of about 50,000, and accept electrons from the flavoprotein NADPH-P-450 reducÃ-ase. Nearly 20 different P-450 proteins have been isolated from rat liver and all appear to be distinct gene products. Levels of the individual proteins are altered by administration of or exposure to a wide variety of chemicals, many of which are carcinogens themselves (including tumor initiators such as the polycyclic hydrocarbons and tumor promoters such as phénobarbital). Mitochondrial P-450s accept electrons from ferridoxins and seem to be primarily involved in anabolic steroid metabolism, although some evidence for roles in carcinogen oxidation has been presented (14). Several reviews and monographs deal with various aspects of the catalytic mechanisms and regulation of the P-450 enzymes